Shwachman-Diamond Syndrome (SDS [MIM 260400]) is an autosomal recessive disorder with clinical features including exocrine pancreatic insufficiency, haematological dysfunction, and skeletal abnormalities1,2,3. Patients with SDS have a high risk of bone marrow failure and are at risk of developing acute myelogenous leukaemia (AML). SDS is the second most common cause of pancreatic insufficiency after cystic fibrosis and involves the failure of development of the exocrine pancreas. Other manifestations include skeletal abnormalities and liver function abnormalities, the latter being notable in young patients.
Many SDS patients present with malabsorption and steatorrhea related to their pancreatic insufficiency. Many such children fail to thrive due to the malabsorption and also due to their disinclination to eat normally because of gastrointestinal upsets. The haematological dysfunction most consistently involves neutropenia but can also present as thrombocytopenia or pancytopenia. Serious consequences for SDS patients include recurring severe infections that can be life threatening if the diagnosis is not made with the provision of prompt treatments. Further, traditional methods for treatment of bone marrow failure are generally not successful in SDS patients at this time but the surveillance and monitoring of the bone marrow to determine the occurrence of myelodysplasia, aplastic anaemia and/or the development of AML do provide some options for intervention.
It is therefore important for the optimum development and overall long term prognosis of these children that they are diagnosed as having SDS as early as possible so that infections may be treated with appropriate interventions, so that blood and bone marrow can be monitored for cellularity (numbers and cell types) and so that pancreatic enzyme supplementation may be instituted to provide adequate or near normal food absorption.
There are other diseases associated with exocrine pancreatic dysfunction, such as Cystic Fibrosis and Pearson Marrow Syndrome, and other diseases such as congenital neutropenia, Blackfan-Diamond Syndrome and Fanconi Anaemia can mimic the haematological manifestations of SDS. It is important, for proper treatment, that SDS is diagnosed as early as possible but at present SDS can only be distinguished from other diseases causing similar symptoms by complex, symptom-based tests which may have to be repeated many times before a conclusion is reached (Rothbaum et al., (2002), J. Pediatrics, v. 141, pp. 266-270; Ginzberg et al., (2000), Am. J. Hum. Genet., v. 66, pp. 1413-1416).
There is therefore a real need for a convenient and definitive test, such as a genetic test or a gene product-based immunological test, to diagnose SDS. Further, as the bone marrow failure aspects are so serious, there is need to provide new options to correct the associated deficiencies. The identification and analysis of the gene that is affected in SDS would provide for such opportunities.
Segregation analysis of an international collection of families of SDS patients supports an autosomal recessive mode of inheritance (Ginzberg et al., (2000), Am. J. Hum. Genet., v. 66, pp. 1413-1416). Previous studies of families with SDS showed that the putative SDS locus mapped to the centromeric region of chromosome 7, to a 1.9 cM interval at 7q114,5. The genetic defect associated with the disease has, however, not previously been identified.